Cisplatin-aar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYSPATIN-AAR (CISPLATIN-AAR)

Composition:

Active substance: cisplatin;

1 vial contains 10 mg or 50 mg of cisplatin (1 mg/mL);

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physico-chemical properties: clear, colorless to pale yellow solution in a glass vial.

Pharmacotherapeutic group. Antineoplastic agents. Platinum compounds. ATC code L01X A01.

Pharmacological properties.

Pharmacodynamics.

Cisplatin has biochemical properties similar to bifunctional alkylating agents. It inhibits DNA synthesis by forming intra- and inter-strand cross-links (cross-links) within DNA strands. Synthesis of protein and RNA is also suppressed, although to a lesser extent.

Although the antitumor effect of cisplatin is primarily associated with inhibition of DNA synthesis, other mechanisms, including increased tumor immunogenicity, may contribute to its antineoplastic activity. The oncolytic effect of cisplatin is comparable to that of alkylating agents. Cisplatin also has immunosuppressive and antimicrobial properties and enhances sensitivity to radiation. The action of cisplatin on cells is independent of the cell cycle phase.

Pharmacokinetics.

Absorption.

Cisplatin is well taken up by the kidneys, liver, and intestine. More than 90% of platinum-containing compounds remaining in the blood are bound (possibly irreversibly) to plasma proteins.

The degree of penetration into cerebrospinal fluid is low, although a significant amount of cisplatin may be found in intracerebral tumors.

Distribution.

Elimination of total platinum from plasma is rapid during the first four hours after intravenous administration, but then proceeds more slowly due to covalent binding to serum proteins. Levels of free platinum decrease with a half-life ranging from 20 minutes to 1 hour, depending on the infusion rate.

Excretion.

Excretion of the free drug and various platinum-containing biotransformation products occurs via urine. Approximately 15–25% of the administered platinum is rapidly eliminated from the body within the first 2–4 hours after cisplatin administration. This early excretion mainly involves predominantly free cisplatin. Within the first 24 hours after administration, 20–80% is excreted, while the remainder consists of substance bound to tissues or plasma proteins.

Clinical characteristics.

Indications.

• Advanced or metastatic testicular cancer;
• advanced or metastatic ovarian cancer;
• advanced or metastatic bladder cancer;
• advanced or metastatic squamous cell carcinoma of the head and neck;
• advanced or metastatic non-small cell lung cancer;
• advanced or metastatic small cell lung cancer;
• treatment of cervical tumors in combination with other medicinal products or radiotherapy.

Cisplatin may be used as monotherapy as well as in combination therapy.

The drug is indicated for the treatment of adults and children.

Contraindications.

• Hypersensitivity to cisplatin or to any component of the medicinal product. Cisplatin may cause allergic reactions in some patients. Its use is contraindicated in patients with a history of allergic reactions to cisplatin or other platinum-containing drugs, or to any component of the product.
• Cisplatin causes nephrotoxicity, which is cumulative; therefore, it is contraindicated in patients with a history of impaired renal function.
• Cisplatin has also been shown to have cumulative neurotoxicity (including ototoxicity); therefore, it should not be administered to patients with a history of hearing impairment. Cisplatin is also contraindicated in patients with myelosuppression and dehydration.
• Breastfeeding period (see section "Use during pregnancy or breastfeeding").
• Concomitant use with yellow fever vaccine and prophylactic therapy with phenytoin.

Special precautions.

Preparation and handling of the drug

As with any other cytotoxic agents, caution should be exercised when handling Cisplatin-AAR. The concentrate must be diluted before administration. Dilution should be performed by trained personnel in a specially designated area under aseptic conditions. Protective gloves should be used. Precautions should be taken to avoid contact of the drug with skin and mucous membranes. If contact with skin occurs, the skin should be immediately washed with soap and water. Sensations of stinging, burning, and redness may occur upon skin contact. Mucous membranes should be thoroughly rinsed with water if contact occurs. After inhalation, dyspnea, chest pain, throat irritation, and nausea may occur.

Pregnant healthcare workers should not handle cisplatin.

Physiological waste and vomitus should be disposed of carefully.

If the solution is cloudy or an insoluble precipitate is present, the vial should be discarded. Damaged vials should be disposed of, taking the same safety precautions as for disposal of contaminated waste. Contaminated waste should be stored in special waste containers (see section "Disposal").

Preparation for intravenous administration.

Withdraw the required amount of solution from the vial and dilute it in at least 1 liter of one of the following solutions:

• 0.9% NaCl solution;
• mixture of 0.9% NaCl solution and 5% glucose solution (1:1) (final concentrations: 0.45% NaCl, 2.5% glucose);
• 0.9% NaCl solution and 1.875% mannitol solution for injection;
• 0.45% NaCl solution, 2.5% glucose solution, and 1.875% mannitol solution for injection.

The solution should always be inspected before administration. If the solution is cloudy or an insoluble precipitate forms, it must not be used. Only clear, particle-free solutions should be used.

Needles and other intravenous administration equipment containing aluminum parts must not be used for the preparation or administration of cisplatin solution.

The undiluted concentrate must not be used.

Disposal.

All materials used in the preparation and administration of, or otherwise coming into contact with cisplatin, should be destroyed in accordance with local regulations regarding the disposal of cytotoxic substances.

Medicinal products must not be disposed of via wastewater or household waste.

Interaction with other medicinal products and other types of interactions.

Nephrotoxic drugs.

Nephrotoxic drugs (e.g., cephalosporins, aminoglycosides, amphotericin B, or contrast agents) and ototoxic drugs (e.g., aminoglycosides) potentiate the nephrotoxic effects of cisplatin. Drugs that are primarily excreted by the kidneys (such as bleomycin and methotrexate) should be used with caution during or after cisplatin treatment, as cisplatin may reduce renal elimination.

When ifosfamide is used in combination with cisplatin or administered after prior cisplatin treatment, the nephrotoxicity of ifosfamide is enhanced.

In several cases, decreased serum lithium concentrations have been observed during combined therapy with cisplatin, bleomycin, and etoposide. Therefore, monitoring of lithium levels is recommended during treatment.

Ototoxic drugs.

Concomitant use of ototoxic drugs (e.g., aminoglycosides and loop diuretics) potentiates the ototoxic effects of cisplatin on hearing function. Except for patients receiving cisplatin doses exceeding 60 mg/m² body surface area and with urine output less than 1000 mL in 24 hours, forced diuresis using loop diuretics should not be performed, as this may lead to renal damage and increased ototoxicity.

Ifosfamide also potentiates the ototoxic effects of cisplatin.

Live attenuated vaccines.

Administration of the yellow fever vaccine is strictly contraindicated due to the risk of developing fatal systemic disease (see section "Contraindications"). Due to the risk of systemic disease, inactivated vaccines are recommended whenever possible.

Oral anticoagulants.

When oral anticoagulants are used concomitantly, regular monitoring of the international normalized ratio (INR) is recommended.

Phenothiazines, antihistamines, and other drugs.

Symptoms of cisplatin ototoxicity (e.g., dizziness, tinnitus) may be masked by concomitant use of antihistamines, buclizine, cyclizine, loxapine, meclizine, phenothiazines, thioxanthenes, or trimethobenzamides.

Anticonvulsants.

In patients receiving cisplatin and anticonvulsants concomitantly, serum concentrations of the latter may decrease to subtherapeutic levels. Pyridoxine + altretamine, combination.

In a randomized clinical trial, it was observed that in patients with progressive ovarian cancer, response to therapy was poorer when pyridoxine combined with altretamine (hexamethylmelamine) was used concomitantly with cisplatin. Paclitaxel.

It has been established that when paclitaxel is administered after cisplatin, the clearance of paclitaxel may decrease by 33%, thereby increasing neurotoxicity.

Antiepileptic agents.

In patients receiving cisplatin and phenytoin concomitantly, the serum concentration of phenytoin may decrease. This is primarily due to reduced absorption of phenytoin and/or enhanced metabolism. In such patients, plasma phenytoin levels should be monitored and the dose adjusted accordingly.

Special precautions for use.

Treatment with cisplatin must be administered under the supervision of a qualified oncologist only in specialized units equipped to provide appropriate monitoring and care. Appropriate resuscitation equipment must be available to manage anaphylactic reactions.

Cisplatin reacts with aluminum, forming a black platinum precipitate. Therefore, the use of instruments containing aluminum (including intravenous infusion systems, needles, catheters, and syringes) should be avoided. For further details, see section "Incompatibilities".

The infusion solution must not be mixed with any other medicinal products or excipients.

Appropriate monitoring and management of treatment and its complications are possible only with an adequate diagnosis and clearly defined treatment regimens.

Nephrotoxicity.

Cisplatin causes severe cumulative nephrotoxic effects, which may be potentiated by concomitant use of aminoglycosides. Before initiating cisplatin therapy and prior to each subsequent treatment cycle, serum creatinine, blood urea nitrogen, creatinine clearance, and serum levels of magnesium, sodium, potassium, and calcium should be monitored. Cisplatin should not be administered more frequently than once every 3–4 weeks. A diuresis of 100 mL/hour or greater minimizes the nephrotoxic effects of cisplatin. Adequate diuresis can be achieved by pre-hydration with 2 L of an appropriate intravenous solution, or by similar hydration after cisplatin administration (recommended: 2500 mL/m² over 24 hours). If hydration alone is insufficient to maintain adequate diuresis, osmotic diuretics (e.g., mannitol) may be administered.

Neuropathy.

Severe neuropathy has been reported. These complications may be irreversible and may manifest as paresthesia, areflexia, loss of proprioceptive sensation, and impaired vibratory sense. Cases of motor function loss have also been reported. Neurological examinations should be performed regularly in patients receiving cisplatin.

Neurotoxicity is known to be cumulative.

Prior to each treatment cycle, the absence of symptoms of peripheral neuropathy should be confirmed.

Ototoxicity.

Ototoxicity has been observed in 31% of patients receiving a single dose of cisplatin at 50 mg/m², manifesting as tinnitus and/or high-frequency hearing loss (4000–8000 Hz). In some cases, hearing loss may occur within the speech frequency range. Ototoxic effects may be more pronounced in children receiving cisplatin therapy. Hearing loss may be unilateral or bilateral and increases in frequency and severity with repeated administration. In rare cases, deafness has been reported after the first dose of cisplatin. Prior or concurrent radiotherapy to the head region increases the risk of ototoxic complications, possibly due to peak plasma concentrations of cisplatin. It is not known whether cisplatin-induced ototoxicity is reversible. Audiograms should be performed before initiating cisplatin therapy and before each subsequent treatment cycle. Vestibular toxicity has also been reported (see section "Adverse reactions").

Allergic reactions.

Anaphylactic reactions have been observed with cisplatin. These reactions may occur within minutes of administration in patients previously exposed to cisplatin and can be managed with adrenaline, glucocorticoids, and antihistamines.

As with other platinum-containing medicinal products, hypersensitivity reactions may occur, most commonly during infusion. Such reactions require immediate cessation of infusion and appropriate symptomatic treatment. Cross-reactions, sometimes fatal, have been reported with all platinum compounds (see sections "Contraindications" and "Adverse reactions").

Liver function and blood counts.

Blood counts and liver function should be monitored regularly.

Potential carcinogenic effects.

In rare cases, acute leukemia in humans has been temporally associated with cisplatin use; these cases were usually linked to concomitant use of other leukemogenic agents.

Cisplatin is a bacterial mutagen and causes chromosomal aberrations in animal cell cultures. Carcinogenicity is possible but has not yet been demonstrated. Cisplatin has teratogenic and embryotoxic effects in mice.

Injection site reactions.

Reactions at the injection site may occur during cisplatin administration. Due to the risk of extravasation, the infusion site should be closely monitored for signs of infiltration. Specific treatment for extravasation reactions has not been established.

Warnings.

This cytostatic agent is more toxic than conventional antineoplastic chemotherapeutic agents.

Renal toxicity, which is primarily cumulative, is severe and requires special precautions during administration (see sections "Method of administration and dosage" and "Adverse reactions").

Nausea and vomiting may be severe and require appropriate antiemetic therapy. Patients should be carefully monitored for ototoxicity, myelosuppression, and anaphylactic reactions (see section "Adverse reactions").

Preparation of the intravenous solution.

Precautions.

As with other potentially toxic agents, appropriate safety measures must be followed when handling cisplatin solution. Accidental exposure may cause skin irritation. Protective gloves are recommended. If the solution comes into contact with skin or mucous membranes, thoroughly rinse with soap and water.

Recommended procedures for handling and disposal of cytostatic agents should be followed.

Prior to administration, the solution should be inspected visually for clarity and absence of particulate matter.

Important information on excipients.

Patients on a sodium-restricted diet should be cautious when using this medicinal product, as it contains 9 mg/mL of sodium.

Use during pregnancy or breastfeeding.

Pregnancy. Cisplatin may have toxic effects on the fetus when administered during pregnancy. Cisplatin should not be used during pregnancy unless there are life-threatening indications. Both male and female patients receiving cisplatin should take appropriate contraceptive precautions during treatment and for at least 6 months after completion of therapy.

Breastfeeding. Cisplatin passes into breast milk; therefore, breastfeeding is contraindicated during cisplatin therapy.

Fertility. Patients who wish to have children after completion of therapy should consult a genetics specialist prior to treatment. Since cisplatin may cause irreversible infertility, men who wish to father children in the future should consider sperm cryopreservation before starting therapy.

Contraception in men and women. Both men and women receiving cisplatin should use effective contraception to prevent conception during treatment and for at least 6 months after therapy.

Ability to drive and use machines.

No studies have been conducted on the effects of cisplatin on the ability to drive or operate machinery. However, the adverse reaction profile (e.g., nephrotoxicity) may negatively affect the ability to drive or operate machinery.

Method of Administration and Dosage.

Dosage.

Adults and Children.

Cisplatin doses are determined based on the underlying pathology, expected response to therapy, and whether cisplatin is used as monotherapy or as part of combination chemotherapy. The dosage regimens listed below are recommended for both adults and children.

For monotherapy, the following treatment regimens are recommended:

• Single dose of 50–120 mg/m² body surface area administered every 3–4 weeks;
• Daily doses of 15–20 mg/m² body surface area administered for 5 consecutive days, repeated every 3–4 weeks.

In combination therapy, lower doses are required. Cisplatin is usually administered at a dose of 20 mg/m² body surface area or higher every 3–4 weeks.

For the treatment of cervical tumors, cisplatin should be used in combination with radiation therapy. Cisplatin is typically administered at a dose of 40 mg/m² body surface area once weekly for 6 weeks.

The next treatment cycle may only be initiated after a comprehensive assessment of the patient's condition (see section "Special Warnings and Precautions for Use").

If renal function impairment or bone marrow suppression occurs, the dose of the drug must be appropriately reduced (see section "Contraindications"). The infusion solution, prepared according to the instructions provided in the section "Special Precautions for Handling," should be administered only by intravenous infusion over 6–8 hours.

Adequate hydration should be provided 2–12 hours before cisplatin administration and for at least 6 hours after the end of the infusion. Hydration is necessary to maintain sufficient diuresis during and after cisplatin administration. In adults, hydration is achieved by intravenous infusion of 0.9% sodium chloride solution or a mixture of 0.9% sodium chloride solution and 5% glucose solution in a 1:1 ratio.

Hydration prior to cisplatin therapy: intravenous infusion of one of the above-mentioned solutions at a rate of 100–200 mL/hour for 6–12 hours, with a total volume of at least 1 liter.

Hydration after drug administration: intravenous infusion of an additional 2 liters of one of the above-mentioned solutions at a rate of 100–200 mL/hour over 6–12 hours.

If urine output remains below 100–200 mL/hour after hydration, forced diuresis may be required. This is achieved by intravenous administration of 37.5 g of mannitol (375 mL of 10% solution) or the use of diuretics (provided renal function is normal).

Mannitol or diuretics should also be administered when the cisplatin dose exceeds 60 mg/m² body surface area.

Patients should drink large amounts of fluids for 24 hours after cisplatin administration to ensure adequate urine output.

Children.

In children, before initiating the next treatment cycle with Cisplatin-AAR, key laboratory parameters (serum creatinine, urea, leukocytes, platelets, audiogram) should return to age-appropriate normal values.

Overdose.

Caution should be exercised to prevent accidental overdose. Symptoms. Acute cisplatin overdose may lead to renal failure, hepatic failure, deafness, ophthalmotoxicity (including retinal detachment), severe bone marrow suppression, intractable nausea and vomiting, and/or neuropathy. Overdose may be fatal.

Treatment. There is no specific antidote for cisplatin overdose. Even hemodialysis performed within 4 hours after overdose has minimal effect on removing cisplatin from the body, as cisplatin binds rapidly and tightly to blood proteins.

In case of overdose, general supportive measures are indicated.

Side effects.

Adverse reactions depend on the dose of cisplatin and may be cumulative in nature.

The most frequently reported adverse reactions (>10% of cases) include: hematological (leukopenia, thrombocytopenia, and anemia), gastrointestinal (anorexia, nausea, vomiting, and diarrhea), hearing disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, hyperuricemia), and fever.

In patients receiving cisplatin as monotherapy, serious ototoxic effects, nephrotoxicity, bone marrow suppression, and hearing organ damage have been reported; these effects are generally dose-dependent and cumulative. Ototoxicity may be more severe in children.

The following frequency criteria were used in assessing adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations.

Common – sepsis; frequency not known – infectiona.

Blood and lymphatic system disorders.

Very common – bone marrow suppression, thrombocytopenia, leukopenia, anemia; frequency not known – Coombs-positive hemolytic anemia.

Benign, malignant, and unspecified neoplasms.

Rare – acute leukemia.

Immune system disorders.

Uncommon – anaphylactoid reactionsb.

Endocrine system disorders.

Frequency not known – increased serum amylase levels, inadequate antidiuretic hormone secretion.

Metabolism and nutrition disorders.

Very common – hyponatremia; uncommon – hypomagnesemia; frequency not known – dehydration, hypokalemia, hypophosphatemia, hyperuricemia, hypocalcemia, tetany.

Nervous system disorders.

Rare – seizures, peripheral neuropathy, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome; frequency not known – cerebrovascular complications, hemorrhagic stroke, ischemic stroke, taste loss, Lhermitte’s sign, cerebral arteritis, myelopathy, autonomic neuropathy.

Eye disorders.

Frequency not known – blurred vision, color vision disturbances, cortical blindness, retrobulbar neuritis, optic disc edema, retinal pigmentation.

Ear and labyrinth disorders.

Uncommon – ototoxicity; frequency not known – tinnitus, deafness.

Cardiac disorders.

Common – arrhythmia, bradycardia, tachycardia; rare – myocardial infarction; very rare – cardiac arrest; frequency not known – cardiac dysfunction.

Vascular disorders.

Common – venous thromboembolism; frequency not known – thrombotic microangiopathy (hemolytic uremic syndrome), Raynaud’s phenomenon.

Gastrointestinal disorders.

Rare – stomatitis; frequency not known – vomiting, nausea, anorexia, hiccups, diarrhea.

Hepatobiliary disorders.

Frequency not known – increased liver enzymes, increased blood bilirubin levels.

Respiratory, thoracic and mediastinal disorders.

Frequency not known – pulmonary embolism.

Skin and subcutaneous tissue disorders.

Frequency not known – rash, alopecia.

Musculoskeletal and connective tissue disorders.

Frequency not known – muscle spasms.

Renal and urinary disorders.

Frequency not known – acute renal failure, renal failurec, tubular dysfunction.

Reproductive system and breast disorders.

Uncommon – impaired spermatogenesis.

General disorders and administration site conditions.

Frequency not known – fever, asthenia, malaise, extravasation at injection sited.

a – infectious complications were fatal in some patients;

b – symptoms of anaphylactoid reactions such as facial swelling, wheezing, bronchospasm, tachycardia, and hypotension are included under anaphylactoid reaction in the frequency list of adverse reactions above;

c – elevated blood urea nitrogen, creatinine, serum uric acid levels, and/or decreased creatinine clearance are indicative of renal failure;

d – local soft tissue toxicity, including cellulitis, fibrosis, and necrosis (common), pain (common), swelling (common), and erythema (common), may result from extravasation.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

After dilution.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the responsibility for storage duration and conditions lies with the user. Generally, the solution should be stored for no longer than 48 hours at room temperature unless dilution is performed under controlled and validated aseptic conditions.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C. Keep out of reach of children. Do not refrigerate. Do not freeze.

Incompatibilities.

Avoid contact with aluminum. Cisplatin reacts with aluminum to form a black platinum precipitate; therefore, avoid using any devices containing aluminum (e.g., intravenous infusion sets, needles, catheters, syringes).

Cisplatin degrades in solutions with low chloride content; chloride concentration should be at least equivalent to 0.45% NaCl.

Due to lack of compatibility studies, Cisplatin-AAR must not be mixed with any other medicinal products.

Antioxidants (e.g., sodium metabisulfite), bicarbonates (sodium bicarbonate), sulfates, fluorouracil, and paclitaxel may inactivate cisplatin in infusion systems.

Cisplatin should only be diluted with solutions specified in the section "Special precautions for handling."

Packaging.

10 ml (10 mg) or 50 ml (50 mg) in a vial; 1 or 10 vials with the instruction for medical use in a cardboard box.

Prescription status. Prescription only.

Manufacturer. VENUS REMEDIES LIMITED / VENUS REMEDIES LIMITED

Manufacturer’s address and location.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India / Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India

Marketing Authorization Holder.

AAR PHARMA FZ-LLC / AAR PHARMA FZ-LLC

Address of Marketing Authorization Holder.

Premises 702, 7th Floor, Building: DSC Tower, P.O. Box – 478837, Dubai, United Arab Emirates / Premises 702, 7th Floor, Building: DSC Tower, Post Box – 478837, Dubai, United Arab Emirates